rs201942775

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_006846.4(SPINK5):c.2795G>A(p.Arg932Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SPINK5
NM_006846.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.623

Variant links:

Genes affected

SPINK5 (HGNC:15464): (serine peptidase inhibitor Kazal type 5) This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

SPINK5 links:

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

FBXO38-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008094579).

BP6

Variant 5-148125778-G-A is Benign according to our data. Variant chr5-148125778-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 529165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK5	NM_006846.4 link	c.2795G>A	p.Arg932Lys	missense_variant	Exon 29 of 33	ENST00000256084.8	NP_006837.2	Q9NQ38-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPINK5	ENST00000256084.8 link	c.2795G>A	p.Arg932Lys	missense_variant	Exon 29 of 33	1	NM_006846.4	ENSP00000256084.7	Q9NQ38-1
SPINK5	ENST00000359874.7 link	c.2885G>A	p.Arg962Lys	missense_variant	Exon 30 of 34	1		ENSP00000352936.3	Q9NQ38-3
FBXO38-DT	ENST00000667608.1 link	n.1257-32036C>T		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00451

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000329

AC:

AN:

249514

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135364

show subpopulations

Gnomad AFR exome

AF:

0.00478

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000115

AC:

168

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.00131

AC:

199

AN:

152300

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00450

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.00136

ESP6500AA

AF:

0.00752

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000505

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ichthyosis linearis circumflexa

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Netherton syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SPINK5-related disorder

Benign:1

May 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.0081

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.58

N;N

REVEL

Benign

0.095

Sift

Benign

0.17

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.52

P;B

Vest4

0.26

MVP

0.22

MPC

0.17

ClinPred

0.018

GERP RS

4.6

Varity_R

0.085

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over